阅读说明：本技术 作为vanin抑制剂的杂芳族化合物 (Heteroaromatic compounds as VANIN inhibitors ) 是由 T·博萨纳 M·J·伯克 B·N·库克 D·T·迪萨尔沃 T·M·小基兰 Y·沈 于 2018-06-08 设计创作，主要内容包括：本发明涵盖式(I)化合物,其中基团A及B在本文中进行定义,其适用于治疗与Vanin相关的疾病,及制备这些化合物的方法,含有这些化合物的药物制剂及其使用方法。<Image he="283" wi="204" file="DDA0002316759990000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention encompasses compounds of formula (I), wherein groups a and B are defined herein, which are useful in the treatment of diseases associated with Vanin, as well as methods of preparing these compounds, pharmaceutical formulations containing these compounds, and methods of use thereof.)

1. A compound of the formula (I),

wherein

A is a group of formula A.1 or formula A.2:

wherein each R¹、R²、R³、R⁴、R⁵And R⁶Independently selected from the group consisting of: H. c_1-4Alkyl, hydroxy or halo substituted C_1-4Alkyl, phenyl and 5-to 6-membered heteroaryl, or

R¹And R²、R³And R⁴Or R⁵And R⁶Together form a 3-to 4-membered carbocyclic ring, an

Wherein

B is selected from the group consisting of formula B.1, formula B.2, and formula B.3:

wherein

R⁷Is H, C_1-3Alkyl, halogen, C_1-3Alkoxy, 5-to 6-membered heteroaryl, or

R⁷Is selected from the group consisting of R^7.a、R^7.bAnd R^7.cGroup of

Wherein

R⁸Selected from the group consisting of C_1-6Alkyl radical, C_3-6Cycloalkyl and 3-to 14-membered heterocyclic group, and

x is CH₂Or O;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein

A is selected from the group consisting of formulas A.1a to A.1f

Or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, wherein

A is selected from the group consisting of formulas A.2a through A.2g

Or a pharmaceutically acceptable salt thereof.

4. A compound as claimed in one or more of claims 1 to 3, wherein

B represents B.1 or B.2

Or a pharmaceutically acceptable salt thereof.

5. A compound as claimed in one or more of claims 1 to 4, wherein

B represents B.2

Or a pharmaceutically acceptable salt thereof.

6. A compound as claimed in one or more of claims 1 to 5, wherein

Each R¹And R²Independently selected from the group consisting of

H、CH₃and-CH₂OH；

Or a pharmaceutically acceptable salt thereof.

7. A compound as claimed in one or more of claims 1 to 5, wherein

R¹And R²Taken together to form a 3-4 membered carbocyclic ring;

or a pharmaceutically acceptable salt thereof.

8. A compound as claimed in one or more of claims 1 to 7, wherein

Each R³And R⁴Independently selected from the group consisting of

H、C_1-3Alkyl and phenyl;

or a pharmaceutically acceptable salt thereof.

9. A compound as claimed in one or more of claims 1 to 7, wherein

R³And R⁴Taken together to form a 3-4 membered carbocyclic ring;

or a pharmaceutically acceptable salt thereof.

10. A compound as claimed in one or more of claims 1 to 9, wherein

R⁵And R⁶Represents H or

R⁵And R⁶Taken together to form a 3-4 membered carbocyclic ring;

or a pharmaceutically acceptable salt thereof.

11. A compound as claimed in one or more of claims 1 to 10, wherein

R⁷Is 5-6 membered heteroaryl or

R⁷Selected from the group consisting of formula R^7.aR is represented by the formula^7.bAnd formula R^7.c(ii) a group consisting of;

or a pharmaceutically acceptable salt thereof.

12. A compound as claimed in one or more of claims 1 to 11, wherein

R⁸Selected from the group consisting of C_1-3Alkyl radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl;

or a pharmaceutically acceptable salt thereof.

13. A compound as claimed in one or more of claims 1 to 12, wherein

X is CH₂Or O;

or a pharmaceutically acceptable salt thereof.

14. A compound of formula I according to claim 1, selected from the group consisting of: examples 14, 15, 16, 17, 21, 22, 25, 26, 37 and 42,

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I as claimed in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

16. A compound according to one or more of claims 1 to 14 or a pharmaceutically acceptable salt thereof for use as a medicament.

17. Use of a compound according to one or more of claims 1 to 14 for the treatment of a patient suffering from: crohn's disease, ulcerative colitis, atopic dermatitis, systemic sclerosis, nonalcoholic steatohepatitis (NASH), psoriasis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft-versus-host disease, psoriatic arthritis, colorectal cancer, or pancreatic cancer-associated emerging diabetes mellitus.

1. Field of the invention

The present invention relates to novel compounds that inhibit Vanin, pharmaceutical compositions containing them and their use as medicaments.

2. Background information

Isoforms 1 and 2 of the Vanin enzyme are single-domain extracellular pantetheinase, which catalyzes the cleavage of pantethine and pantetheine to pantothenic acid and cysteamine, respectively (Martin, Immunogenetics, (5-6.2001), Vol.53, No. 4, p.296-306). Cysteamine production has been associated with oxidative increases in tissue stress caused by decreased glutathione content, a condition characteristic of many pathological conditions, including IBD (Xavier, nature.2011, 6/15; 474(7351):307-17), cancer (Sosa, aging research reviews, (2013, 1/12, 1, 376-90) and diabetes (Lipinski, Journal of diabetes and its complications, (2001, 7-8, 15, 4, 203-10).

Increased activity of Vanin-1 in the gut epithelium has been implicated in promoting tissue damage and inflammation in murine models by reducing tolerance to oxidative stress (Naquet, Biochem Soc Trans.2014 8; 42(4): 1094-; (Berrouyer, Molecular and cellular biology, (8. 2004) Vol.24, No. 16, pp.7214-24); (Berryer, The Journal of experimental media, (2006, 12, 25), Vol 203, No 13, p 2817-27); (Pouyet, Inflummatory bowel diseases, (1 month 2010) volume 16, phase 1, pages 96-104). Homozygote VNN1 Knockout (KO) mice lack appreciable amounts of cysteamine in blood and tissues and show glutathione-mediated tissue tolerance to oxidative stress (berrouyer, The Journal of experimental media, (2006, 12/25) vol 203, vol 13, p 2817-27). In addition, these mice were protected from intestinal injury in TNBS, DSS and schistosome-induced colitis models (Berryer, The Journal of experimental media, (2006, 12/25) Vol.203, No. 13, p.2817-27; Pouyet, Influmatory bowewel diseases, (2010, 1/16, No. 1, p.96-104; Martin, The Journal of clinical intervention, (2004, 2/2), Vol.113, No. 4, p.591-7). Given that rodents lack Vanin-2, the only source of cysteamine was from Vanin-1, the protective phenotype of VNN1 KO mice was attributed to the lack of cysteamine.

In humans, it has been observed that Vanin-1 is up-regulated in the intestinal epithelium in tissue sections from UC and CD patients, and that functional polymorphisms in the regulatory region of the VNN1 gene leading to increased expression of VNN1 are associated with increased susceptibility to IBD (P ═ 0.0003 heterozygote versus wild type) (Gensollen, inflimatory bowel diseases, (2013, month 10), vol 19, No. 11, P2315-25).

In addition, upregulation of Vanin-1 activity in skin and Blood has been associated with the development and severity of fibrosis in patients with systemic sclerosis (Kavian, Journal of immunology (Baltimore, Md.:1950), (20161015) Vol 197, No. 8, pp 3326 and 3335), and elevated levels of Vanin-1 have been observed in chronic juvenile idiopathic thrombocytopenia (Zhang, Blood, (2011 4/28/p) Vol 117, No. 17, pp 4569-79), psoriasis, and atopic dermatitis (Jansen, the Journal of inflammatory disease, (2009 9/p) Vol 129, No. 9, pp 2167-74).

Increased expression and activity of Vanin-1 also exists in New diabetes related to pancreatic Cancer and is used as a biomarker (Kang, Cancer Letters (New York, NY, United States) (2016),373 (2)), 241-.

WO2018011681 discloses Vanin inhibitors for the treatment of a range of diseases, such as crohn's disease and ulcerative colitis.

The problem to be solved by the present invention is to provide novel compounds which act as inhibitors of the Vanin enzyme, preferably as inhibitors of the Vanin-1 enzyme.

It has been surprisingly found that the compounds of the invention have

Potent Vanin-1 inhibitor activity, preferably exhibiting inhibition of VNN-1

IC₅₀[nM]<100, particularly preferred is IC₅₀[nM]<10。

In addition, the compounds of the present invention exhibit the ability to facilitate their pharmacological profile (e.g., high solubility) and often desirable pharmacokinetic properties (e.g., metabolic stability).

Summary of The Invention

It has surprisingly been found that the above-mentioned problems are solved by the compounds of the formula I according to the invention.

In a first general embodiment, there are provided compounds of formula (I)

Wherein A is:

wherein each R1, R2, R3, R4, R5 and R6 is independently H, C_1-4Alkyl or C substituted by hydroxy or halogen_1-4Alkyl, phenyl, 5-to 6-membered heteroaryl or R1 and R2, R3 and R4 or R5 and R6 together form a 3-to 4-membered carbocyclic ring, and

wherein B is:

wherein R7 is H, C_1-3Alkyl, halogen, C_1-3Alkoxy, 5-to 6-membered heteroaryl, or

Wherein R8 is C_1-6Alkyl radical, C_3-6Cycloalkyl or heterocycle, and X is CH₂Or O; or a pharmaceutically acceptable salt or hydrate thereof.

In one aspect of the first general embodiment, there is provided a compound of formula (I)

Wherein A is:

or a pharmaceutically acceptable salt or hydrate thereof.

In another aspect related to the first general embodiment, there is provided a compound of formula (I), wherein B is:

or a pharmaceutically acceptable salt or hydrate thereof.

In another aspect related to the first general embodiment, there is provided a compound of formula (I), wherein B is:

or a pharmaceutically acceptable salt or hydrate thereof.

In another aspect related to the first general embodiment, there is provided a compound of formula (I), wherein a is:

or a pharmaceutically acceptable salt or hydrate thereof.

In another aspect related to the first general embodiment, there is provided a compound of formula (I), wherein B is:

or a pharmaceutically acceptable salt or hydrate thereof.

In another aspect related to the first general embodiment, there is provided a compound of formula (I), wherein B is:

or a pharmaceutically acceptable salt or hydrate thereof.

In a second general embodiment, there is provided a compound selected from the group consisting of:

stereochemistry at position 3 of the pyrrolidine ring of enantiomerically pure compounds is uncertain.

Or a pharmaceutically acceptable salt or hydrate thereof.

In one aspect related to the second general embodiment, the compound is:

examples 20 and 22

Or a pharmaceutically acceptable salt or hydrate thereof.

In a third general embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the first embodiment or related embodiments thereof, or a pharmaceutically acceptable salt thereof.

In a fourth general embodiment, there is provided a method of treating a disease selected from the group consisting of: crohn's disease, ulcerative colitis, atopic dermatitis, psoriasis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, asthma, allergic rhinitis, atopic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft-versus-host disease, psoriatic arthritis, colorectal cancer, and pancreatic cancer-associated emerging diabetes mellitus, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of the first embodiment or related embodiments thereof, or a pharmaceutically acceptable salt thereof.

In a fifth general embodiment, there is provided a method of making a compound according to any one of the first or related embodiments thereof, by the method shown below.

Accordingly, the present invention relates to compounds of formula I

Wherein

A is a group of formula A.1 or formula A.2:

wherein each R¹、R²、R³、R⁴、R⁵And R⁶Independently selected from the group consisting of: H. c_1-4Alkyl, hydroxy or halo substituted C_1-4Alkyl, phenyl and 5-to 6-membered heteroaryl, or

R¹And R²、R³And R⁴Or R⁵And R⁶Together form a 3-to 4-membered carbocyclic ring, an

Wherein

B is selected from the group consisting of formula B.1, formula B.2, and formula B.3:

wherein

R⁷Is H, C_1-3Alkyl, halogen, C_1-3Alkoxy, 5-to 6-membered heteroaryl, or

R⁷Is selected from the group consisting of R^7.a、R^7.bAnd R^7.cGroup of

Wherein

R⁸Selected from the group consisting of C_1-6Alkyl radical, C_3-6Cycloalkyl and 3-to 14-membered heterocyclic group, and

x is CH₂Or O;

or a pharmaceutically acceptable salt thereof.

Description of the preferred embodiments

In another embodiment of the invention, A represents a group of formula A.1.

In another embodiment of the invention

A is selected from the group consisting of formulas A.1a to A.1f

Or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, a is formula a.1a.

In another embodiment of the invention, a is formula a.1b.

In another embodiment of the invention, a is formula a.1c.

In another embodiment of the invention, a is of formula a.1d.

In another embodiment of the invention, a is formula a.1e.

In another embodiment of the invention, a is formula a.1f.

In another embodiment of the invention, a is selected from the group consisting of formula a.1b or formula a.1c.

In another embodiment of the invention, a is selected from the group consisting of formula a.1a or formula a.1d.

In another embodiment of the invention, a is selected from the group consisting of formula a.1e or formula a.1f.

In another embodiment of the invention, A represents a group of formula A.2.

In another embodiment of the invention

A is selected from the group consisting of formulas A.2a through A.2g

Or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, a is formula a.2a.

In another embodiment of the invention, a is formula a.2b.

In another embodiment of the invention, a is formula a.2c.

In another embodiment of the invention, a is formula a.2d.

In another embodiment of the invention, a is formula a.2e.

In another embodiment of the invention, a is formula a.2f.

In another embodiment of the invention, a is formula a.2g.

In another embodiment of the present invention, a is selected from the group consisting of formula a.2a and formula a.2b.

In another embodiment of the present invention, a is selected from the group consisting of formula a.2c and formula a.2d.

In another embodiment of the present invention, a is selected from the group consisting of formula a.2d and formula a.2e.

In another embodiment of the present invention, a is selected from the group consisting of formula a.2f and formula a.2g.

In another embodiment of the invention

B represents B.1 or B.2

In another embodiment of the invention

B represents B.1

In another embodiment of the invention

B represents B.2

In another embodiment of the invention

B represents B.3

Another embodiment of the present invention is a compound of formula IA or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula IB, or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula IC or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula ID or a pharmaceutically acceptable salt thereof.

In another embodiment of the invention

Each R¹And R²Independently selected from the group consisting of

H、CH₃and-CH₂OH；

In another embodiment of the invention

R¹Selected from the group consisting of H, CH₃and-CH₂Group R consisting of OH^1a。

In another embodiment of the invention

R¹Is R^1.bAnd R is^1.bRepresents H.

In another embodiment of the invention

R¹Is R^1cAnd R is^1cRepresents CH₃。

In another embodiment of the invention

R¹Is R^1вAnd R is^1вrepresents-CH₂OH。

In another embodiment of the invention

R²Selected from the group consisting of H, CH₃and-CH₂Group R consisting of OH^2a。

In another embodiment of the invention

R²Is R^2.bAnd R is^2.bRepresents H.

In another embodiment of the invention

R²Is R^2сAnd R is^2сRepresents CH₃。

In another embodiment of the invention

R²Is R^2dAnd R is^2drepresents-CH₂OH。

In another embodiment of the invention

R¹Or R²Represents H.

In another embodiment of the invention

R¹And R²Taken together to form a 3-4 membered carbocyclic ring.

In another embodiment of the invention

R¹And R²Together forming a cyclopropyl group.

In another embodiment of the invention

R¹And R²Together forming a cyclobutyl group.

In another embodiment of the invention

Each R³And R⁴Independently selected from the group consisting of

H、C_1-3Alkyl groups and phenyl groups.

In another embodiment of the invention

R³Is R^3aAnd R is^3aSelected from the group consisting of

H、C_1-3Alkyl groups and phenyl groups.

In another embodiment of the invention

R³Is R^3bAnd R is^3bRepresents H.

In another embodiment of the invention

R³Is R^3cAnd R is^3cIs phenyl.

In another embodiment of the invention

R³Is R^3dAnd R is^3dSelected from the group consisting of methyl, ethyl and propyl.

In another embodiment of the invention

R⁴Is R^4aAnd R is^4aSelected from the group consisting of

H、C_1-3Alkyl groups and phenyl groups.

In another embodiment of the invention

R⁴Is R^4bAnd R is^4bRepresents H.

In another embodiment of the invention

R⁴Is R^4cAnd R is^4cIs phenyl.

In another embodiment of the invention

R⁴Is R^4dAnd R is^4dSelected from the group consisting of methyl, ethyl and propyl.

In another embodiment of the invention

R³Or R⁴Represents H.

In another embodiment of the invention

R³And R⁴Represents H.

In another embodiment of the invention

R³And R⁴Taken together to form a 3-4 membered carbocyclic ring.

In another embodiment of the invention

R³And R⁴Together forming a cyclopropyl group.

In another embodiment of the invention

R³And R⁴Together forming a cyclobutyl group.

In another embodiment of the invention

R⁵And R⁶Represents H or

R⁵And R⁶Taken together to form a 3-4 membered carbocyclic ring.

In another embodiment of the invention

R⁵And R⁶Represents H.

In another embodiment of the invention

R⁵And R⁶Taken together to form a 3-4 membered carbocyclic ring.

In another embodiment of the invention

R⁵And R⁶Together forming a cyclopropyl group.

In another embodiment of the invention

R⁵And R⁶Together forming a cyclobutyl group.

In another embodiment of the invention

R⁷Is 5-6 membered heteroaryl or

R⁷Selected from the group consisting of formula R^7.aR is represented by the formula^7.bAnd formula R^7.c(ii) a group consisting of;

in another embodiment of the invention

R⁷Is R^7dAnd R is^7dSelected from the group consisting of C_1-3Alkyl, halogen and C_1-3Alkoxy groups.

In another embodiment of the invention

R⁷Is R^7eAnd R is^7eIs selected from the group consisting of R^7a、R^7bAnd R^7cAnd (c) groups of (a).

In another embodiment of the invention

R⁷Is R^7fAnd R is^7fRepresents a 6-membered heteroaryl group.

In another embodiment of the invention

R⁷Is R^7gAnd R is^7gRepresents a pyridyl group.

In another embodiment of the invention

R⁷Is R^7hAnd R is^7hRepresents a 5-membered heteroaryl group.

In another embodiment of the invention

R⁸Selected from the group consisting of C_1-3Alkyl radical, C₃-C₆Cycloalkyl and 3-6 membered heterocyclyl;

in another embodiment of the invention

R⁸Is R^8aAnd R is^8aSelected from the group consisting of methyl, cyclopropyl and oxetanyl.

In another embodiment of the invention

R⁸Is R^8bAnd R is^8bIs methyl.

In another embodiment of the invention

R⁸Is R^8cAnd R is^8cIs an oxetanyl group.

In another embodiment of the invention

R⁸Is R^8dAnd R is^8dIs cyclopropyl.

In another embodiment of the invention

X is CH₂Or O.

In another embodiment of the invention

X is CH₂。

In another embodiment of the invention

X is O.

The following table presents further embodiments i.1 to I.9 of the compounds of formula I:

I.1	R1b	R2a
			I.2	R1b	R2b
I.3	R1b	R2c
			I.4	R1b	R2d
I.5	R1a	R2b
			I.6	R1c	R2b
I.7	R1d	R2b
			I.9	R3b	R4a
I.10	R3b	R4b
			I.11	R3b	R4c
I.12	R3b	R4d
			I.13	R4b	R3a
I.14	R4b	R3c
			I.15	R3b	R3d

the following table presents further embodiments i.16 to i.21 of the compounds of formula I:

I.16	A.1	B.1
			I.17	A.1	B.2
I.18	A.1	B.3
			I.19	A.2	B.1
I.20	A.2	B.2
			I.21	A.2	B.3

A、B、R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸and any and each of the definitions of X may be combined with each other.

A preferred embodiment of the present invention are compounds of formula (I),

wherein

A is a group of formula A.1 or formula A.2:

b is selected from the group consisting of formula B.1, formula B.2, and formula B.3:

each R¹And R²Independently selected from H, CH₃and-CH₂OH;

each R³And R⁴Independently selected from H, C_1-3Alkyl and phenyl or R³And R⁴Together form a cyclopropyl group;

R⁵and R⁶Represents H or

R⁵And R⁶Together form a cyclopropyl group;

R⁷is 6-membered heteroaryl or

R⁷Selected from the group consisting of formula R^7.aR is represented by the formula^7.bAnd formula R^7.c(ii) a group consisting of;

R⁸is selected from the group consisting ofC_1-3Alkyl radical, C_3-6Cycloalkyl and 3-6 membered heterocyclyl;

x is CH₂Or O

Or a pharmaceutically acceptable salt thereof.

Yet another preferred embodiment of the present invention are compounds of formula (I),

wherein

A is a group of formula A.1 or formula A.2:

b is selected from the group consisting of formula B.1, formula B.2, and formula B.3:

each R¹And R²Independently selected from H, CH₃and-CH₂OH;

each R³And R⁴Independently selected from H, C_1-3Alkyl and phenyl radicals or

R³And R⁴Together form a cyclopropyl group;

R⁵and R⁶Represents H or

R⁵And R⁶Together forming a cyclopropyl group.

R⁷Is pyridyl or

R⁷Selected from the group consisting of formula R^7.aR is represented by the formula^7.bAnd formula R^7.c(ii) a group consisting of;

R⁸is R^8aAnd R is^8aSelected from the group consisting of methyl, cyclopropyl and oxetanyl.

X is CH₂Or O

Or a pharmaceutically acceptable salt thereof.

Yet another preferred embodiment of the present invention are compounds of formula (I),

wherein

A is the number A.2 of the compound,

b is the number of B.2,

R¹and R²Represents hydrogen, and is represented by the formula,

R³and R⁴Represents hydrogen and

R⁵and R⁶Together forming a cyclopropyl group.

R⁷Is R^7.a。

Yet another preferred embodiment of the present invention are compounds of formula (I),

wherein

A is the number A.1 of the compound,

b is the number of B.2,

R¹and R²Represents hydrogen, and is represented by the formula,

R³and R⁴Together form a cyclopropyl group

R⁷Is R^7.a。

Yet another preferred embodiment of the present invention are the compounds of formula I above selected from the group consisting of: